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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Matrix metalloproteinases-1 and -8 improve the distribution and efficacy of an oncolytic virus
Wilson Mok1, Yves Boucher, Rakesh K Jain
1Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
Abstract:
Oncolytic viral vectors show enormous potential for the treatment of many solid tumors. However, these vectors often suffer from insufficient delivery within tumors, which limits their efficacy in both preclinical and clinical settings. We have previously shown that tumor collagen can significantly hinder diffusion, and that its degradation can enhance the distribution and efficacy of an oncolytic herpes simplex virus (HSV) vector. Here, we identify two members of the matrix metalloproteinase (MMP) family of enzymes, MMP-1 and MMP-8, which can modulate the tumor matrix and enhance HSV delivery and efficacy. We show that overexpression of MMP-1 and MMP-8 in the human soft tissue sarcoma HSTS26T leads to a significant depletion of tumor-sulfated glycosaminoglycans. This increases the hydraulic conductivity of these tumors and enhances the flow of virus during injection. In control tumors, injected virus accumulates primarily in the periphery of the tumor. In contrast, we observed a more widespread distribution of virus around the injection site in MMP-1- and MMP-8-expressing tumors. Due to this enhanced vector delivery, MMP-expressing tumors respond significantly better to oncolytic HSV treatment than control tumors. Thus, these findings introduce a new approach to improve the delivery and efficacy of oncolytic viral vectors: modulation of tumor glycosaminoglycans to enhance convection.
Insights
Matrix metalloproteinases (MMPs), specifically MMP-1 and MMP-8, enhance oncolytic virus delivery by degrading tumor glycosaminoglycans. This improves viral distribution and boosts the efficacy of oncolytic herpes simplex virus (HSV) treatment for solid tumors.
Area of Science:
- Oncology
- Virology
- Biochemistry
Background:
- Oncolytic viral vectors hold promise for solid tumor treatment but face challenges with tumor penetration.
- Previous research indicated tumor collagen impedes viral vector diffusion, and its degradation can improve efficacy.
- Effective delivery of oncolytic viruses within tumors is crucial for maximizing therapeutic outcomes.
Purpose of the Study:
- To identify specific matrix metalloproteinases (MMPs) that can enhance the delivery and efficacy of oncolytic herpes simplex virus (HSV) vectors.
- To investigate the mechanism by which MMPs improve viral vector distribution within solid tumors.
- To evaluate the impact of MMP-mediated tumor matrix modulation on the therapeutic response to oncolytic HSV.
Main Methods:
- Overexpression of MMP-1 and MMP-8 in human soft tissue sarcoma HSTS26T cells.
- Assessment of tumor-sulfated glycosaminoglycan depletion and changes in hydraulic conductivity.
- Evaluation of viral distribution following injection in tumors with and without MMP overexpression.
- Comparison of the therapeutic efficacy of oncolytic HSV in MMP-expressing versus control tumors.
Main Results:
- Overexpression of MMP-1 and MMP-8 led to significant depletion of tumor-sulfated glycosaminoglycans.
- This depletion increased tumor hydraulic conductivity, enhancing viral flow during injection.
- MMP-expressing tumors showed a more widespread viral distribution compared to control tumors.
- Tumors engineered to express MMPs demonstrated significantly improved responses to oncolytic HSV treatment.
Conclusions:
- MMP-1 and MMP-8 can modulate the tumor matrix by depleting glycosaminoglycans, thereby enhancing oncolytic viral vector delivery.
- Improved convection of viral vectors through the tumor interstitium leads to better therapeutic efficacy.
- Targeting tumor glycosaminoglycans represents a novel strategy to improve oncolytic virotherapy for solid tumors.
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